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Published in , the research was led by the London School of Hygiene & Tropical Medicine, Fiocruz-Pernambuco, Federal University of Pernambuco, State University of Pernambuco, and the Pan American Health Organization.

The relationship between Zika virus and microcephaly is widely assumed to be causal because of strong evidence of an association. However, evidence so far comes from case reports, case series, modelling studies, and preliminary reports from cohort studies - none of which have included appropriate control groups.

The study was requested by the Brazilian Ministry of Health to investigate the causes of the microcephaly epidemic that was declared a Public Health Emergency of International Concern in 2016.

It included all infants born with microcephaly delivered in eight public hospitals in Pernambuco State in North Eastern Brazil between 15 January and 2 May 2016. For each case, two controls were selected. Controls were the first two infants born the following morning without microcephaly in one of the eight hospitals. Controls and cases were matched for region of residence and expected date of delivery.

Blood samples from cases and controls were collected and samples of cerebrospinal fluid were collected from cases with microcephaly. Samples were tested for Zika virus and Zika virus antibodies. Blood samples were collected from mothers and analysed for Zika and dengue virus. Infants with microcephaly had their head circumference measured and most underwent brain imaging.

24 of 30 (80%) mothers of infants with microcephaly had Zika virus infection, compared with 39 of 61 (64%) mothers of controls. 13 of 32 cases (41%) tested positive for Zika virus infection in blood or cerebrospinal fluid samples, and none of the 62 controls tested positive for Zika virus infection in blood samples.

A high proportion of mothers also tested positive for dengue and other infections such as cytomegalovirus (a type of herpes), rubella, and toxoplasma but there was no significant difference between mothers of cases and controls. Additionally, only seven of the 27 cases with microcephaly who had a brain scan had brain abnormalities, suggesting that congenital Zika virus syndrome can be present in neonates with microcephaly and no brain abnormalities.

Laura Rodrigues, Professor of Infectious Disease Epidemiology at the London School of Hygiene & Tropical Medicine and an author on the study, said:

"Although there is a strong scientific consensus that Zika virus is a cause of microcephaly, the early findings from this case control study are the missing pieces in the jigsaw in terms of proving the link. Crucially, this paper also suggests testing newborns for anti-zika antibody, IgM, in blood or liquor as a good option for an agreed test to diagnose children with Congenital Zika Syndrome - something not currently available. It also clearly shows that even babies with normal brain image can have the condition."

The authors warn that preliminary analyses can overestimate the strength of an association, so the true size of the effect needs to be treated with caution. The full study, which will include 200 cases and 400 controls will help quantify the risk more precisely and shed light on the role of co-factors.

Professor Rodrigues added: "When complete, the study, along with other ongoing research, will provide vital information on any role cofactors might have in the epidemic. Cohort studies conducted by the School and other institutions will establish the level of risk for mothers infected with the virus, how babies with the condition develop and the impact and costs to families and society. This will enable health services to target resources effectively, and ensure families affected by this devastating condition receive the support they need."

The authors add that detecting the presence of Zika virus or antibodies in blood and cerebrospinal fluid is the only current method of testing for Zika virus in newborns but the reliability of this method, especially when infections occur early in pregnancy, is not fully understood. The authors say that these limitations might partly explain why 19 (59%) of microcephaly cases were not confirmed as positive for Zika virus. 

Study author Dr Thália Velho Barreto de Araújo, Federal University of Pernambuco, Recife, Brazil, said:

"A high proportion of mothers of newborns with and without microcephaly had been infected with Zika virus, reflecting the rapid spread of Zika infection in this region. However, when we compared laboratory confirmed Zika virus infection in newborns with and without microcephaly, we found that about half of the cases with microcephaly had laboratory confirmed Zika virus infection, compared to none of the healthy controls.

"Our findings suggest that Zika virus should be officially added to the list of congenital infections alongside toxoplasmosis, syphilis, varicella-zoster, parvovirus B19, rubella, cytomegalovirus, and herpes. However, many questions still remain to be answered including the role of previous dengue infection."

The study was funded by the Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations.

Publication

• Thalia Velho Barreto de Araújo, Laura Cunha Rodrigues, Ricardo Arraes de Alencar Ximenes, Demócrito de Barros Miranda-Filho, Ulisses Ramos Montarroyos, Ana Paula Lopes de Melo, Sandra Valongueiro, Maria de Fátima Pessoa Militão de Albuquerque, Wayner Vieira Souza, Cynthia Braga, Sinval Pinto Brandão Filho, Marli Tenório Cordeiro, Enrique Vazquez, Danielle Di Cavalcanti Souza Cruz, Cláudio Maierovitch Pessanha Henriques, Luciana Caroline Albuquerque Bezerra, Priscila Mayrelle da Silva Castanha, Rafael Dhalia, Ernesto Torres Azevedo Marques-Júnior, Celina Maria Turchi Martelli. . The Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(16)30318-8.

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